Animal Models to Assess Efficacy of Countermeasures for SM-lnduced Toxicity The overall objective of this project is to identify the most efficacious therapeutics to treat SM-induced toxicity. The specific goals of this research project are to establish and validate animal models of Sulfur Mustard (SM) toxicity following inhalation, dermal, and ocular exposure. Once animal models are established, the efficacy of existing therapeutics and potential new therapeutics to attenuate SM-induced toxicity identified in Research Projects 2, 3 and 4 will be examined. The efficacy of new formulations and alternative routes of exposure (i.e., inhalation) will also be examined. Formulations and dose routes showing the most promise for therapeutic efficacy will undergo more definitive efficacy evaluations conducted under Good Laboratory Practice Guidelines to support any future Investigational New Drug Applications to the U.S. Food and Drug Administration (FDA). This project has the following specific aims: 1) Develop and validate small animal models of SM-induced toxicity following inhalation, dermal, and ocular exposure. Provide tissue and excreta samples to Research Project 1 for biomarker identification; 2) Determine the uptake and distribution of SM administered dermally and by inhalation; 3) Examine the efficacy of currently existing therapeutics with demonstrated efficacy against SM-induced toxicity or with potential efficacy based on SM-mechanisms of action in the validated animal models. Determine the efficacy and pharmacokinetics of existing therapeutics reformulated for enhanced drug delivery. Examine the efficacy of new potential therapeutics identified during mechanistic studies conducted in Research Projects 2, 3, and 4; and 4) Conduct more extensive efficacy studies on the most promising therapeutic-dose route combination under GLP guidelines. Develop the miniature swine animal model for definitive efficacy testing of promising formulations to treat SM-induced dermal lesions. These proposed studies are significant because they will identify and provide definitive efficacy studies on new therapeutics or alternate formulations of existing therapeutics for the treatment of SMinduced toxicity. Results of definitive efficacy studies conducted under Good Laboratory Practice Guidelines can support Investigative New Drug Applications to the Food and Drug Administration.